Maintaining and promoting healthy cognitive functions, of which memory is a most important one, is one of the major goals of mental health research. Diseases, stress, injury and aging can lead to cognitive and memory impairments. It is estimated that up to one third of adults will experience a gradual decline in cognitive function known as mild cognitive impairment as they age. Furthermore, a number of diseases such as Alzheimer's disease, autism, mental retardation are associated with memory impairments. Thus, minimizing or preventing cognitive and memory impairments is a very important goal in mental health. A principal approach toward this goal is to understand the physiological mechanisms of memory formation, persistence and storage and identify molecular mechanisms and targets that can be used to enhance memory, not only for potentiating normal functions but also for developing strategies that may prevent or reverse memory loss. Newly learned information that will become a long-term memory remains in a labile state for some time and becomes a long- term memory through a process of stabilization, known as memory consolidation. Using contextual fear conditioning types of memories in rats, we have recently found that hippocampal administration of the growth factor insulin like growth factor 2 (IGF-2) leads to potent memory enhancement and also increases memory persistence. Using inhibitory avoidance (IA) and other tasks like fear extinction and social transmission of food preference in rats and mice, this proposal aims at identifying the molecular mechanisms and brain circuitry of the IGF-2-mediated memory consolidation and enhancement. It will also test whether other members of the IGF system (IGF-1 and insulin) have memory-enhancing effects. Finally, with preclinical and translational goals in mind, given that IGF-2 readily passes the blood brain barrier, it will determine whether systemic treatments with IGF-2 are effective in enhancing memories retention and persistence and whether the IGF-2-dependent effect alters memory flexibility. Results from these studies should advance our knowledge of neural mechanisms that may be employed to achieve memory enhancement and to treat cognitive impairments.